Abstract
Simple SummaryCancer-associated mortality largely depends on metastatic dissemination. Metastasizing cancer cells exhibit drastic phenotypic changes, including the ability to migrate, invade surrounding tissues, survive in the bloodstream, adapt to different microenvironments, and resist to therapeutic treatments. These changes depend on the genetic reprogramming orchestrated by relatively few players (transcription factors). Among the components of the dimeric transcription factor AP-1, the nuclear oncoprotein Fra-1 is strongly implicated in metastasis mechanisms. Therefore, Fra-1, along with other proinvasive transcription factors, represents an ideal therapeutic target. However, as for other DNA-binding proteins, the design of inhibitory drugs is hampered by the structural features of Fra-1. In this Review, after summarizing the Fra-1 functions and mechanisms of accumulation in invasive tumors, we survey the possible application of multiple strategies and emerging technologies aimed at the inhibition of Fra-1 expression and activity, to prevent metastatic dissemination and therapeutic resistance. The genetic and epigenetic changes affecting transcription factors, coactivators, and chromatin modifiers are key determinants of the hallmarks of cancer. The acquired dependence on oncogenic transcriptional regulators, representing a major determinant of cancer cell vulnerability, points to transcription factors as ideal therapeutic targets. However, given the unavailability of catalytic activities or binding pockets for small-molecule inhibitors, transcription factors are generally regarded as undruggable proteins. Among components of the AP-1 complex, the FOS-family transcription factor Fra-1, encoded by FOSL1, has emerged as a prominent therapeutic target. Fra-1 is overexpressed in most solid tumors, in response to the BRAF-MAPK, Wnt-beta-catenin, Hippo-YAP, IL-6-Stat3, and other major oncogenic pathways. In vitro functional analyses, validated in onco-mouse models and corroborated by prognostic correlations, show that Fra-1-containing dimers control tumor growth and disease progression. Fra-1 participates in key mechanisms of cancer cell invasion, Epithelial-to-Mesenchymal Transition, and metastatic spreading, by driving the expression of EMT-inducing transcription factors, cytokines, and microRNAs. Here we survey various strategies aimed at inhibiting tumor growth, metastatic dissemination, and drug resistance by interfering with Fra-1 expression, stability, and transcriptional activity. We summarize several tools aimed at the design and tumor-specific delivery of Fra-1/AP-1-specific drugs. Along with RNA-based therapeutics targeting the FOSL1 gene, its mRNA, or cognate regulatory circRNAs, we will examine the exploitation of blocking peptides, small molecule inhibitors, and innovative Fra-1 protein degraders. We also consider the possible caveats concerning Fra-1 inhibition in specific therapeutic contexts. Finally, we discuss a recent suicide gene therapy-based approach, aimed at selectively killing the Fra-1-overexpressing neoplastic cells.
Highlights
The oncogenic transcription factors (TFs) were originally envisaged as ideal targetsThe oncogenic transcription factors (TFs) were originally envisaged as ideal targets for anticancer therapies [1], and encouraging preclinical/clinical results were obtained by for anticancer therapies [1], and encouraging preclinical/clinical results were obtained targeting the TFs harboring binding sites for small molecules, such as the Stat3 SH2-phosby targeting the TFs harboring binding sites for small molecules, such as the Stat3 SH2phorylation domain and the hormone-binding domains of the steroid receptors
Among FOS family members, the transcription factor Fra-1 is a major driver of cancer cell invasion, EMT (Epithelial-to-Mesenchymal Transition), and metastasis
Multiple AP-1 binding sites mediate the FOSL1 positive autoregulation, which amplifies the effect of Fra-1 posttranslational accumulation
Summary
The oncogenic transcription factors (TFs) were originally envisaged as ideal targets. Right: the FOS-family members (c-Fos, FosB, Fra-1, Fra-2), which can only heterodimerize proteins. X-shaped alphacrystal structure of c-Fos/c-Jun DNA-bound bZIP domain (PDB: 1FOS). The blue-colored predicted alpha-helix colored predicted alpha-helix (from Ser101 to Pro175) encompasses the bZIP DNA-binding domain,. As for the other FOS proteins, the Fra-1 structure can be modeled (with high to very high confidence) only for the 70–80-aa region encompassing the DNA-binding bZIP region, while most of the protein appears intrinsically unstructured (Figure 1B). Various lines of evidence, including the genetic inactivation of individual JUN and FOS family members in onco-mouse models, show that individual AP-1 proteins can exhibit cell context-dependent oncogenic or tumor suppressor roles, as highlighted in a seminal review entitled: “AP-1: a double-edged sword in tumorigenesis” [4])
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